Multi-arm or star polymer architectures are a new generation of branched polymeric materials that include a single core and multiple connecting arms or chains. Star polymers usually have highly condensed and globular structures, tailorable size and large surface areas for conjugation of therapeutic agents and imaging agents, which makes them suited as potential delivery platforms. Various star polymer carriers have been synthesized and utilized for the delivery of small-molecule chemotherapeutics, including doxorubicin (conjugation) and paclitaxel (encapsulation), proteins, such as insulin, as well as genetic materials, such as DNAs and siRNAs.
Multi-arm polymers can be synthesized under a broad range of conditions with low polydispersity using reversible addition-fragmentation chain transfer polymerization (RAFT). During the RAFT process, the polymers derived keep their “livingness” so that it is possible to prepare well-defined polymers. Moreover, the RAFT process is tolerant toward a range of functional groups thus minimizing the need for additional synthetic pathways to install protecting groups on the monomers being used.
Nitric oxide is a cell signaling molecule involved in many mammalian physiological processes and pathological conditions. The effects of nitric oxide on tissues are highly concentration dependent. Low levels of nitric oxide synthase (NOS) overexpression in cancer cells is frequently associated with enhanced tumor cell invasion and growth and an increase in aerobic glycolysis capacity, i.e., the Warburg effect. However, high concentrations of nitric oxide can inhibit NF-kB activity, which regulates cell proliferation, and down-regulating Bcl-xL expression, which modulates apoptotic pathways. Nitric oxide has been shown to radio-sensitize cancers, inhibit DNA repair mechanisms, inhibit hypoxia-induced drug resistance, and reverse the epithelia to mesenchyma phenotype transition of tumors. Nitric oxide has a half-life of about 5 seconds in vivo, due to rapid reaction of the unpaired electron with hemoglobin and heme-ferrous iron and subsequent decomposition into nitrate. Therefore, nitric oxide donating prodrugs have been developed for anti-cancer therapy, such as JS-K. JS-K is a glutathione S-transferase-activated (GST-activated) nitric oxide prodrug, releasing nitric oxide in vitro, inhibiting the proliferation of cancer cells, including breast cancer cells, non-small-cell lung cancer cells and myeloma cells. Because GSTs are also expressed in normal mammalian organs, the potential toxicity and carcinogenicity of JS-K must not be overlooked.
The potential for dose-dependent carcinogenicity of nitric oxide-releasing agents has limited their development as systemically administered anti-cancer agents. The effective and safe use of these agents requires that the nitric oxide release be highly confined to tumorigenic tissues and exposure to sub-therapeutic doses must be minimized. The tissue distribution of small molecule drugs is typically non-specific, with increased exposure in clearance organs, such as the kidneys and liver. To overcome this challenge, a drug molecule may be conjugated to a targeted delivery system so that it will be preferentially released in tumorigenic cells. Water-soluble polymers have been utilized for the preparation of drug conjugates that display significant advantages in pharmaceutical applications, including low toxicity, excellent water solubility, and tissue targeting through passive (e.g., enhanced permeation and retention effect) or receptor-based targeting. Despite the targeted nature of these carriers in intravenous applications, healthy tissues will still receive substantial exposure due to long residence in the clearance organs and circulatory system. This problem can be partially overcome by delivering nanoconjugates directly to the primary tumor and the draining lymphatics. This approach can greatly improve the response in locally advanced cancers, since the nanoconjugate and method of administration can confine the drug to only the tumor and the lymph nodes draining the tumor. An issue in the design of these drug delivery systems is the carrier must be very stable within the extravascular space, which limits the use of micelles and liposomes, and it should be under 50 nm in size for rapid clearance from the injection site. Structured polymers such as dendrimers meet these requirements, but dendrimers such as polyamidoamine (PAMAM) constructs are not biodegradable and have limited capacity for water-insoluble drugs. Multi-arm or star polymers are branched nanoscale materials that have a compact structure, globular shape, and large surface area that make them highly suited for targeted drug delivery when built with non-toxic and biodegradable polymers.
Cisplatin is a water soluble, platinum-based chemotherapeutic that has been widely used for many years in the clinic as a first-line chemotherapy for head and neck squamous cell carcinoma, ovarian cancer, and non-small cell lung cancer. The major side effect of cisplatin infusion chemotherapy is renal toxicity, which limits its use. The toxicity of cisplatin is dependent on the maximum concentration of free drug in the plasma. Slow and confined release of cisplatin into tumors can largely alleviate these toxicities.
Geldanamycin (GA), an ansamycin benzoquinone antibiotic, is an HSP90 inhibitor that exhibits both antimicrobial activity and anticancer activity. The anti-cancer activity of GA was first determined in the 1970s against L1210 murine leukemia and KB cells; despite its encouraging in vitro and in vivo activity in early preclinical studies, its development was limited due to its significant hepatotoxicity in vivo. Nevertheless, two of its C-17 analogues, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), have been pursued in the clinic due to their enhanced activity, decreased liver toxicity, and increased water solubility (17-DMAG). Further, 17-AAG was found to have efficacy in both HER2 positive (SKBr3) and negative (MCF7) breast cancer cell lines, and deplete the HER2 oncoprotein in the SKBr3 cell line. Due to its increased water solubility and equivalent activity, the development of 17-DMAG over 17-AAG has grown in interest. With the combined reports of HSP90 overexpression in melanoma, its function in the metastasis of melanoma, and activity against HER2 positive breast cancer, a lymphatically targeted geldanamycin derivative-star polymer conjugate was developed for the localized delivery to both locally advanced melanoma and breast cancers.
Charge is an important factor for lymphatic uptake of nanoparticles. Studies with proteins, liposomes, dendrimers, and PLGA-nanospheres have demonstrated that negatively charged particles have increased lymphatic uptake compared to neutral to positively charged particles, due in part to the electrostatic repulsions between the negatively charged particles and the extracellular matrix, which is primarily negatively charged. Also, negatively charged particles are retained longer, and to a greater extent by lymph nodes. Manipulation of the size, molecular weight, charge, and surface chemistry of polymers, such as multi-arm polymers, may affect the pharmacokinetics and tissue distribution of these materials after injection, e.g., by in the intravenous, subcutaneous, peritumoral, percutaneous, interstitial, peri-tumoral, intraocular, intratumoral, submucosa, mucosa, intradermal, peritoneal, inhalation routes, or by pulmonary instillation, ingestion, transdermal application, or administration to cavities, tissues, organs, or spaces within the body.